The overall goal of the proposed research is to develop, optimize, and evaluate novel nuclear imaging methods for quantifying pancreatic islet cell mass in vivo. Approaches to noninvasively assay islet cell mass are greatly needed because these would lead to a better understanding of the pathogenesis of diabetes, provide an early diagnostic marker for type 1 and type 2 diabetes, and accelerate the development and evaluation of new therapies. Through considerable efforts by many investigators, a number of radiotracers targeting various islet receptors or processes have been evaluated for islet imaging but have thus far not proven useful for quantifying islet mass in humans. The small size of islets, their low abundance, and their scattered distribution create considerable challenges for non-invasive methods to quantify islet cell mass. This proposal outlines a new interdisciplinary approach using optical and nuclear imaging with antibodies highly specific for the surface of islet cells that were recently developed in the Beta Cell Biology Consortium. In order to overcome the slow radiotracer clearance and high non-target tissue background that has hindered previous antibody-based imaging agents, we will use a pretargeting approach proven useful in tumor targeting and preliminary studies of islet cell imaging. This pretargeting strategy overcomes the prior limitations associated with antibody-based imaging by employing a three-step protocol of sequentially injecting the antibody, then a clearance agent, and lastly the radio labeled effectors. The ability of our pretargeting and clearance approach to image islet mass will be evaluated using unique pre-clinical models that combine bioluminescence imaging of the beta cell, specific beta-cell ablation, and multimodal imaging with co-registration of tomographic images to spatially delineate increased or decreased islet mass.